Interleukin 10 (IL-10) is a cytokine produced by T lymphocytes, B lymphocytes and macrophages that was first identified based on its ability to inhibit interferon gamma and IL-2 synthesis (Fiorentino, et al., J. Exp. Med. 170:2081-2089 (1989); Moore, et al., Science 248:1230-1252 (1990); Vieira, et al., Proc. Nat'l Acad. Sci. USA 88:1172-1177 (1991); O'Garra, et al., Internat. Immunol. 2:821-828 (1990); Fiorentino, et al., J. Immunol. 147:3815-3822 (1991)). IL10 has since been shown to have a variety of biological functions and has been extensively studied for possible therapeutic use in connection with inflammatory bowel disease and autoimmune diseases such as psoriasis, rheumatoid arthritis, and multiple sclerosis (Li, et al., World J. Gastroenterol. 10(5):620-625 (2004)).
IL10 has also received attention as a potential treatment for cancers in which inflammation is known to be a predisposing factor, particularly cancers of the colon. 129/SvEv Rag2−/− mice, which lack mature lymphocytes, have been shown to develop colitis and colon cancer following infection with a widespread enteric bacterial mouse pathogen Helicobacter hepaticus (Erdman, et al., Am. J. Pathol. 162:691-702 (2003); Erdman, et al., Cancer Res. 63:6042-6050 (2003)). The inflammatory bowel disease and carcinoma that develop in H. hepaticus-infected Rag2−/− mice are abrogated by treatment with IL10-competent regulatory cells (Erdman, et al., Cancer Res. 63:6042-6050 (2003)). Other studies using immune-deficient mice have revealed similar protective and therapeutic effects mediated by CD4+ regulatory cells in mice with colitis (Powrie, Immunity 3:171-174 (1995); Maloy, et al., J. Ex. Med. 197:111-119 (2003)). Interestingly, adoptive transfer of regulatory cells lacking IL10 is not protective, but instead exacerbates the malignant phenotype such that 100% of male recipients rapidly develop mucinous colonic tumors that invaded the peritoneal cavity (Erdman, et al., Cancer Res. 63:6042-6050 (2003)).
The development of IL10 as a therapeutic has been limited, in part, by its short plasma half life. In this regard, it has been suggested that IL10 is only effective for about 30 minutes following administration and attempts have been made to increase its duration of action by coupling it to other proteins with longer half lives (Gerard, et al., J. Exp. Med. 177:547 (1993); U.S. Pat. No. 6,410,008; U.S. Pat. No. 6,403,077). Other problems are that there has not been any reliable method of predicting which types of tumors, if any, IL10 is likely to be effective against and its complex biological effects make the routine administration of very large doses of IL10 undesirable.